KR100394382B1 - Pharmaceutical composition consisting of natural human α-interferon - Google Patents

Abstract

Use of natural human alpha-interferon for the preparation of a medicament in liquid form to be administered through peroral route at dosages comprised between 100 UI and 500 UI/day, for therapy of viral infections, in particular viral hepatitis, neoplasia and immune diseases in humans and animals.

Description

Pharmaceutical composition consisting of natural human α-interferon

α-, β-, γ-interferon is administered by injection, which is useful for treatment. α-interferon is the most commonly used (1). In recent studies on the treatment of acute or chronic viral hepatitis (2), only α-interferon is allowed as a monotherapy.

"Viral hepatitis" refers to at least five etiologies with other causative agents, namely A, B, C, D, E.

The tendency of treatment is to treat this etiology with a fixed dose depending on the patient's overall condition, hepatitis type and other factors. In general, for chronic hepatitis (B. C. D) in interferon treatment, nearly standardized clinical and biochemical parameters were obtained. Although interferon activity has not yet been concentrated for acute infections, treatment with α-interferon in hepatitis C can slow the rate at which the disease becomes chronic.

The course of treatment involves administering the recombinant α-interferon once daily via the subcutaneous route, up to about 5,000,000 I.U per day in particular cases up to 9,000,000 I.U.

The duration of the course of treatment is 6 months to 1 year (average 9 months).

In many cases, side effects occur during the course of treatment. Some patients, especially those with severe severity or physiologically severe injuries, are unable to adapt to such treatment regimens and are discontinued. Side effects include fever, nausea, vomiting, fatigue, pain and depression.

In addition to the large amounts of active substances (8,000 new annually in Italy and 300,000 annually worldwide) and parenteral administration (outpatient-only hospitals), there is a significant cost of treatment due to the need for hospitalization with side effects. do.

Finally, in the case of chronic viral hepatitis, the only alternative to interferon treatment is liver transplantation.

Clinically, there is a tendency to increase doses and lengthen the course of treatment (3), but serious side effects as seen in clinical data; Low adaptability of the patient; High treatment costs are a problem. Garcia et al. (5) reported that the cost to a healed patient would be between 700,000 and 2,000,000 pounds in British pounds, and Capri S (6) would cost 70,000,000 Lit for each patient when treated with interferon.

Thus, the interferon composition used to treat hepatitis is not appropriate.

In addition, the clinical results showed better therapeutic effects in patients who were not the main targets of treatment, such as young patients, patients in early stages of disease, patients infected with genotype virus 2 or 3, or patients with low virulence. Was outstanding. Conversely, the therapeutic effect was low in patients who actually needed therapeutic treatments (slow responding patients) because more than 50 individuals had active hepatitis of aggressive type. Therefore, patients requiring immediate interferon treatment have a low probability of success.

The present invention relates to a pharmaceutical composition for oral administration consisting of natural human α-interferon isolated from lymphocytes or leukocyte cells. In particular the composition is useful for treating viral infections, in particular viral hepatitis, nephrogenesis and immunodeficiency symptoms. The interferon effect dose is much lower than the dose used for parenteral administration.

Applicants of the present invention have discovered a pharmaceutical composition for oral administration consisting of natural human α-interferon isolated from lymphocytes or leukocyte cells, the interferon effect dosage is much lower than the dosage used for parenteral administration. The composition is an active substance having a therapeutic effect similar to that of the existing composition, which can solve the disadvantages of the existing composition while maintaining the chemical-physical, biological, and pharmacological properties.

The composition is a solution at a concentration of 100 to 500 I.U / ml, suitably about 150 I.U / ml, most suitably about 1 ml in a single unit dose.

The composition acts to activate defense mechanisms against viral infection, tumor growth, and to stimulate the immune response.

Natural interferons are used to increase therapeutic success for recombinant interferons obtained by cloning a single subtype.

Leukocyte and lymphocyte interferon have the same therapeutic properties, but interferon is more beneficial in leukocytes. In fact, it can be obtained from stabilized cell lines without the help of a blood donor.

Processes for purifying interferon are known in the art, see, eg, US Pat. No. 4,732,683; Cantell K. and Hirvonen S. Texas Reports on Biology and Medicine, Vol. 35, p. 138, 1977; Zoon K.C. et al., Science 207, p. 527, 1980.

Oral administration is more suitable for patients, easier to define dosages, lower dosages, stop antigen attack, induce delivery and amplification signal mechanisms, and greater than 100 dosages compared to parenteral dosage forms. Can be lowered.

Lowering the dose can eliminate the toxic effects, use the drug more efficiently to meet the treatment needs, and significantly reduce the cost of treatment.

Active materials are readily available; Good cleanliness standards for single containers; The dose taken can be made clear; The active substance can be absorbed directly into the oral-nasal mucosa and can be easily prevented from swallowing; The formulation is made in small volumes (1 ml) so that all patients can be safely and easily administered. The tablets are likely to be swallowed because they must be contained in the mouth until it is completely dissolved.

In addition, the composition of the present invention can be conveniently used at home or at work can control chronic diseases requiring evaluation, long-term treatment (more than 1 year), and prevent recurrence, to prevent viral etiology.

The compositions of the present invention can be used with other drugs to achieve synergistic effects and optimize the course of treatment.

The following clinical studies show the therapeutic effect. Quantitative-quantitative qualitative-quantitative qualitative analysis of individual human α-interferon in patients with hepatitis or other diseases by comparing the electrophoretic pattern of proteins with the concentrations of IgG, IgA, and IgM before oral treatment and two and two weeks after treatment Can be seen.

Patients responding to treatment with a 450 I.U / day dose increased HgVe antigen and seroconversion by increasing IgA and IgM levels with decreasing α2 globulin and β-globulin, decreasing IgG, and decreasing IgG / IgA ratio (seroconvert) In other words, there is an opportunity to safely alleviate the etiology.

On the other hand, individuals who respond to the same treatment with increased α1-globulin moiety and increased IgG, IgA, IgM and decreased albumin serum concentrations can also be seroconverted for long periods of time.

In addition, individuals with increased IgG at the IgG / IgA ratio and reduced IgM at the IgA / IgM ratio showed resistance to treatment.

Monitoring these variables helps to formulate treatment strategies and implement clinical practice in the clinic.

Clinical study in healthy individuals

Table 1 below shows various treatment procedures.

Changes in the biological response induced for the course of treatment can be measured in blood samples taken at different time periods. In particular, activity was measured for daily doses, single and multiple doses, and duration of the course of treatment of the active ingredient.

In data analysis, natural human α-interferon derived from lymphocytes or leukocytes administered orally via low doses can regulate the expression of membrane antigens in blood mononuclear cells of healthy individuals (depending on duration and dose of treatment). It can be seen that there is. In particular, according to the therapeutic procedure, the pharmaceutical composition appears to be able to increase the CD4 and CD8 cell population. There is also evidence of increased expression of cellular activity markers with the DR antigen and interleukin 2 receptor.

As can be seen in Tables 2 and 3, the treatment course of 450 U / day X 5 days (Experiment B) yields better results. In fact, CD3, CD4, DR1, and CD25 lymphocytes (% and absolute) increased. This increase is in many cases excellent in T ₃ , T ₄ and T ₅ and decreased in T ₆ and T ₇ .

However, with the same dose, the duration of the treatment course is short (1 day; experiment a), where the percentage of mononuclear cells in the blood, and the absolute value, are less likely to interfere (Tables 4 and 5). Indeed, in this experiment, the mean% value was increased, but the absolute T, CD8, histocompatibility antigen-II lymphocyte values were not increased at T ₃ .

Other experimental conditions show that the increase in immune response is slowed.

Thus, natural human α-interferon derived from lymphocytes or leukocyte cells administered at low doses via oral plays an important role in regulating the immune response to afferent rather than centrifugal, and is used to treat infectious diseases and other immunodeficiency diseases. It can be used therapeutically.

Clinical Study in Hepatitis Patients

Virus hepatitis B

Fourteen patients with chronic viral hepatitis B with an average age of 4 to 59 years were used in the randomized study.

All patients were previously treated for several months to years with steroids or steroid-azothiopurine, and these patients had no beneficial effect on clinical symptoms or disease, particularly biochemical variables of liver cirrhosis.

Treatment with a single dose of 150 I.U / day is performed immediately after the discontinuation of prior treatment, and the therapeutic effect is a change in the immune response; Changes in blood tissues; Changes in serum markers of viral infections and changes in biopsies of liver biopsy samples are monitored and monitored.

The observation period varied from 15 months to 32 months, and the results are summarized in the following table.

1) Temporary disruption of liver biochemical function (eg 2-3-fold increase in alanineaminetransferase (ALT) level) without clinical signs of disease exacerbation in all patients during the first 3-6 weeks of treatment;

2) symptoms persist for 4-6 weeks;

3) strong activation of the immune system was observed even after treatment in all patients;

4) Seven patients had HBV DNA, HBeAg removed from serum and stable seroconversion:

5) one patient has increased HBcAg than eigenvalues;

6) Nine other patients had reduced titers significantly.

Thus, in 50% of patients, the disease was statically reduced.

Virus hepatitis C

Standard treatment of viral hepatitis C was by oral use of α-interferon.

Six patients with active chronic hepatitis C were treated with oral 150 IU / day α-interferon after steroid treatment was discontinued.

It has various observation periods (same as the treatment period) of 19 to 69 weeks. Generally well tolerated for treatment, all patients tolerated physical exercise, increased appetite and vitality.

After 19 weeks of discontinuation, one patient had a bioclinical alleviation of the disease, but none of the patients had normalized transaminases during the observation period due to increased joint pain.

The results are shown in Table 2-5.

Related literature

1) Howard M. et al. Le Scienze n.311 Vol LIII 72-80 (1994).

2) Saracco G., Rizzetto M. Biomed. Pharmacother. 49 (2), 55-57 (1995).

3) Kasahara A.K., et al., Hepatology; 21, 291-297 (1995).

4) Paoletti A. et al .; Clin. Ter. 146 (5), 343-349 (1995).

5) Garcia De Ancos J.L. et al .; J. Hepatol. 11: s 11-s 18 (1990).

6) Capri S. Adis International, Milano, pp 41-49 (1994).

7) Bianchi F.B., La rivista del medico pratico, Ott. (suppl. 5) (1995).

Claims (4)

A liquid pharmaceutical composition for treating viral hepatitis in humans and animals, wherein the natural human α-interferon is composed of 100 IU to 500 IU / day, and is administered via oral liquid pharmaceutical composition for treating viral hepatitis. The liquid pharmaceutical composition according to claim 1, wherein the interferon is obtained from lymphocyte cell culture. The liquid pharmaceutical composition according to claim 1, wherein the interferon is obtained from lymph cell culture. The liquid pharmaceutical composition according to claim 1, wherein the drug has a single dose of 1 ml.